1. Field of the Invention
The present invention relates to iodinated X-ray contrast media. More particularly, the present invention is directed to periodinated borane and carborane cage molecules for use as diagnostic X-ray contrast media.
2. Technology Review
Over the years, a number of iodinated compounds have been developed and brought to market as X-ray contrast media ("XRCM"). Successful X-ray contrast media share several common characteristics. For example, XRCM must be stable in vivo and must be pharmacologically inert. Other factors also influence effectiveness of XRCM, such as percentage by weight of radiopaque species, e.g. iodine, per molecule, water solubility, and toxicity. The toxicity of the compounds can be related to lipophilicity (hydrophobicity), ionic strength, osmolality, and viscosity.
The above factors are often interrelated. For instance, molecules with increasing numbers of iodine atoms become increasingly more lipophilic, which makes them less water soluble and more likely to be toxic. However, the number of iodine atoms in a single molecule has been shown to have a direct correlation to the clarity of X-ray images obtained. Thus, high iodine content is a desired feature. Iodobenzoic acids were initially used because they had low toxicity; however, fully iodinated benzoic acids were not practical since other functional groups were necessary to give the molecule the desired solubility and pharmacological properties.
Functionalized triiodinated benzene molecules are well known XRCM. In general, it has been necessary to functionalize three of the carbons on the benzene ring for solubilization and detoxification. To obtain more than the usual three iodine atoms on a single molecule, dimers, trimers and polymers of the iodobenzene moiety have been prepared. This has increased the number of iodine atoms, but it also changes the shape of the molecule (to more linear) and increases its viscosity. Increased viscosity causes difficulty in administration and may cause toxicity problems, but dimers have generally been found to be less toxic than the corresponding monomer, presumably due to the decrease in osmolality.
Solubility of the iodinated molecules can be greatly increased by having ionized functionalities on the molecule (e.g. carboxylic acids, amino groups); however, osmolality of the body fluids is affected by the high dosage concentrations needed. High osmolality can cause toxicity. For this reason recent development of X-ray contrast agents has been focused on nonionic, water soluble iodinated compounds.
The functionalized triiodinated benzene-based XRCM that have been brought successfully to market needed very low toxicity because of the large doses required to provide sufficient radiopacity for X-ray contrast. While not wishing to be bound by theory, it is believed that conventional triiodinated benzene-based XRCM simply function as carriers of iodine. Since these conventional X-ray contrast media have from 30% to 70% iodine w/w, dramatic improvements in the contrast obtained in diagnostic X-ray studies may be obtained with contrast agents containing higher percentages of iodine by weight.
It will be appreciated that it would be a significant advancement in the art to provide iodinated diagnostic X-ray contrast media possessing high percentages of iodine by weight, but which also have good solubility and low osmolality.
Such iodinated diagnostic X-ray contrast media are disclosed and claimed herein.